PROJECT SUMMARY Oral cancer pain results from activation of primary afferent neurons by cancer-secreted mediators. My previous work demonstrated that mice bearing tongue cancers induced by 4-nitroquinoline-1-oxide (4NQO)- carcinogenesis exhibit nociceptive behavior and trigeminal ganglia neurons (TGNs) innervating the tongue become hyperexcitable. Oral cancer cells also secrete neurotrophic factors that induce neuronal sprouting into the cancer, while local neurotransmitter release from TGNs innervating the cancer has been linked to carcinogenesis. I hypothesize that oral cancer and sensory neurons interact, such that, oral cancer induces sensitization, sprouting and plasticity in neurons, and efferent neuronal activity promotes oral carcinogenesis. In support of my hypothesis, I demonstrated, using an oral cancer xenograft model that nerve axotomy suppressed oral squamous cell carcinoma growth in the hindpaw. To test my hypothesis and to prepare me for an independent research career, I propose in the K99 phase to gain skills in high-resolution microscopy, quantitative analysis, cancer cell biology and oral histopathology. Specifically, I will characterize the type, distribution, sprouting features and development over time of sensory nerves innervating the oral cancer microenvironment during 4NQO-carcinogenesis (Aim 1). In Aim 2, I will determine the reciprocal impact of neuron-cancer communication using cell cultures in vitro. I propose to use these skills in the R00, to study the differential impact of primary afferent neurons on oral cancer pain and carcinogenesis through inhibition of cancer-induced neuronal sprouting and ablation of TGN subpopulations in an oral cancer mouse model. The successful completion of the proposed experiments and training program will further my knowledge in the relationship between sensory neurons and cancer, as well as develop skills I need to pursue an independent research career.